2,6-dimethyl-3,5-dimethoxycarbonyl-4-(5&#39;-trimethylsilyl-2&#39;-furyl)-1,4-dihydropyridine

ABSTRACT

2,6-dimethyl-3,5-dimethoxycarbonyl-4-(5&#39;-trimethylsilyl-2&#39;-furyl)-1,4-dihydropyridine which has the formula ##STR1## This compound exhibits a hypotensive activity.

FIELD OF THE INVENTION

The present invention relates to the art of organic synthesis, morespecifically, to 1,4-dihydropyridine derivatives and, more particularly,to2,6-dimethyl-3,5-dimethoxycarbonyl-4-(5'-trimethylsilyl-2'-furyl)-1,4-dihydropyridine.

The above-mentioned 1,4-dihydropyridine derivatives have hypotensive andcoronarodilating effects and some of them are useful in medicine.

PRIOR ART

The most widespread 1,4-dihydropyridine derivatives is2,6-dimethyl-3,5-dimethoxycarbonyl-4-(O-nitrophenyl)-1,4-dihydropyridine(Nifedipine) possessing hypotensive and coronarodilating effects(Arzneium.-Forsch, V.32, 1982, E. Kusano, J. Asano, K. Takeda, J.Matsumoto, A. Ebihar. "Hypotensive Effect of Nifedipine in HypertensivePatients with Chronic Renal Failure", pp. 1575-1580).

Though Nifedipine is widely used in the medical practice, it is unstablein light and highly toxic.

The known 1,4-dihydropyridine derivatives containing silicon in the3,5-ester group are substantially inferior to Nifedipine as regardstheir hypotensive activity (Eur. J. Med. Chem., V.18, No.2, 1983, R.Tacke, A. Bentlage, R. Towart, E. Moller, "Sila-Analogues ofNifediphine-Like dialkyl2,6-dimethyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxylates", pp.155-161).

Among 1,4-dihydropyridine derivatives known in the art is2,6-dimethyl-3,5-dimethoxycarbonyl-4-(2'-furyl)-1,4-dihydropyridinewhich also displays a hypotensive activity, though considerably lowerthan that of Nifedipine (Khimiko-pharmaceuticheskij Zhournal, No.6,1979, V. V. Kastron, G. Ya. Dubur, R. O. Vitolin', A. A. Kimenis"Synthesis and pharmacological activity of4-furyl-1,4-dihydropyridines", pp.57-62).

The above-mentioned derivatives of 1,4-dihydropyridine, though possess ahypotensive effect, this effect is not lasting which necessitates theirrepeated administration during the day's period. Furthermore, Nifedipinehas a high toxicity.

DISCLOSURE OF THE INVENTION

The present invention is directed to the provision of such a derivativeof 1,4-dihydropyridine which would exhibit a protracted hypotensiveeffect and, at the same time, would have a low toxicity.

This object is accomplished by a derivative of 1,4-dihydropyridinewhich, according to the present invention, is2,6-dimethyl-3,5-dimethoxycarbonyl-4-(5'-trimethylsilyl-2'-furyl)-1,4-dihydropyridineof the formula ##STR2##

This compound is novel. We have found that this compound displays aprotracted hypotensive effect and has a relatively low toxicity.

This compound comprises a crystalline substance of a yellowish shade andm.p. of 158°-159° C. It is well soluble in methanol, ethanol,chloroform, acetone and substantially insoluble in water. This compoundis stable both in the crystalline state and as solutions. When solid,upon storage in the light this compound does not change its UV spectrumwithin a year's period. In a alcoholic solution of the concentration of5×10⁻⁵ mol the UV spectrum remained unchanged for 6 months. At the sametime, in the UV spectrum of Nifedipine under similar conditions amaximum of the oxidized form of Nifedipine is observed already within 6hours.

This compound is prepared by the method comprising condensation ofmethyl ester of acetoacetic acid, ammonia and 5-trimethylsilylfurfurolin solution of methanol. Furthermore, this compound can be obtained bycondensation of methyl ester of acetoacetic acid, methyl ester ofβ-aminocrotonic acid and 5-trimethylsilylfurfurol in a medium of anorganic solvent. The reaction is carried out under normal pressure underheating. The product is obtained in a good yield.

The starting components employed for the preparation of theabove-mentioned compound are known and available substances.

The pharmacological study of the compound according to the presentinvention was conducted in comparison with a preparation of the sameseries employed in clinical practice, viz. Nifedipine.

In experiments on spontaneously hypertensive rats the compound accordingto the present invention upon a single administration (10 mg/kg instomach) caused reduction of systolic arterial pressure. The maximumhypotensive effect (by 21 %) was observed by the 6-th hour afteradministration of the compound, after 24 hours the pressure was reducedby 17 % as compared to the initial value. A single-time administrationof the compound for 5 days in the dose of 10 mg/kg into the stomachcaused the maximum reduction of the pressure (by 22 %) on the 6-th day,i.e., one day after discontinuation of administration of the compound. Areduced pressure was observed on the 3-rd day (by 10 %) afterdiscontinuation of the administration. In comparison with Nifedipine itwas clear that the latter was superior to the compound of the presentinvention by the 1-st hour after administration, by the 6-th hour bothcompounds showed the same hypotensive effect and 24 hours after theadministration the compound of the present invention still produced thehypotensive effect, whereas in the rats administered with Nifedipine thesystolic pressure returned to the initial level. Therefore, the compoundaccording to the present invention is superior over Nifedipine asregards the duration of its effect upon a single and repeatedadministration and it provides a less pronounced effect on the heartrate. The data of the studies are shown in Table 1 hereinbelow. For thepurpose of comparison this Table also shows the data for2,6-dimethyl-3,5-dimethoxycarbonyl-4-(2'-furyl)-1,4-dihydropyridinewhich is an analog of the compound according to the present invention asregards its chemical structure.

                  TABLE 1                                                         ______________________________________                                        Effect of compounds on arterial pressure in experiments                       on spontaneously hypertensive rats                                                    Dose,   Hypotensive effect, %, after                                  Compound  mg/kg     1 hr   6 hrs  24 hrs                                                                              48 hrs                                ______________________________________                                        Of this   10        13     21     17    --                                    invention 20        --     30     39    28                                    Analog    10        12      7      0     0                                    Nifedipine                                                                              10        34     23      0     0                                    ______________________________________                                    

As it is seen from Table 1, the compound according to the presentinvention has a more lasting hypotensive effect than the analog andNifedipine.

We have found that this compound in the doses of 10 and 20 mg/kg inexperiments on spontaneously hypertensive rats (SHR) upon a peroraladministration either lowers the heart rate or does not change it. Asregards this effect, the compound according to the present invention ispositively distinguished from Nifedipine causing tachycardia.

The acute toxicity of the compound according to the present invention,that of Nifedipine and the analog was studied on white nondescript miceupon an intraperitoneal administration. The mice were observed for 10days. The mean lethal dose (LD₅₀) was determined by the Litchfield andWilcoxon method. The administration of the compound according to thepresent invention in doses of up to 1,000 mg/kg did not cause death ofthe mice. The data on the study of the acute toxicity are shown in Table2 hereinbelow.

                  TABLE 2                                                         ______________________________________                                        Acute toxicity                                                                Compound              LD.sub.50, mg/kg                                        ______________________________________                                        Of the present invention                                                                            above 1,000                                             Analog                2,900                                                   Nifedipine            185 (119-287)                                           ______________________________________                                    

It is seen from Table 2 hereinabove that the compound according to thepresent invention has a low toxicity as compared to Nifedipine. Thoughthe analog has a low toxicity as well, its hypotensive properties aresubtantially lower than those of the compound of the present invention.

Taking into consideration a clearly pronouced and protracted hypotensiveeffect of the compound of the present invention, as well as its lowtoxicity and a high stability as compared to the prior art preparationNifedipine, it can be recommended for the treatment of hypertensivedisease. The duration of the effect produced by the compound accordingto the present invention makes it possible to assume that thetherapeutic effect can be attained by a single-time adiministration ofthe compound a day.

BEST MODE FOR CARRYING OUT THE INVENTION

The above-identified compound, viz.2,6-dimethyl-3,5-dimethoxycarbonyl-4-(5'-trimethylsilyl-2'-furyl)-1,4-dihydropyridineshould be prepared by the method comprising condensation of methyl esterof acetoacetic acid, methyl ester of β-aminocrotonic acid and5-trimethylsilylfurfurol in the emdium of methanol. The reaction iscarried out at the temperature of boiling of the reaction mixture undernormal pressure. The completion of the reaction is determined by thethin-layer chromatography method. On completion of the reaction thereaction mixture is cooled and the resulting precipitate of the desiredproduct is separated. The yield of the product after crystallization is61.7 %. The product thus obtained corresponds to the above-givenformula.

For a better understanding of the present invention, an exampleillustrating preparation of the compound according to this invention isgiven hereinbelow.

EXAMPLE

2.45 g (1.45 mmol) of 5-trimethylsilylfurfurol, 1.68 g (1.45 mmol) ofacetoacetic acid methyl ester and 1.66 g (1.45 mmol) of β-aminocrotonicacid methyl ester are boiled for 3 hrs in 10 ml of methanol. A yellowprecipitate is formed upon cooling. The precipitate is washed withhexane to give 4.5 g (92.5 %) of the compound. After recrystallizationfrom methanol 3 g (61.7 %) of the product are obtained. M.p. 158°-159°C. R_(f) 0.70 (hexane-chloroform-ethylacetate, 1:1:1). UV spectrum,λ_(max), nm (1g): 234 (4.46), 352 (3.92). IR spectrum, cm⁻¹ : 1,659;1,715; 3,365. PMR spectrum, δ, ppm: (4-H); 5.64 g (3'-H, furan). J=2 Hz;6.45 d (4'-Hλ, furan). J=2 Hz.

Found, %: C 59.17: H 6.41; N 3.84. C₁₈ H₂₅ NO₅ Si. Calculated, %: C59.48; H 6.93; N 3.85.

INDUSTRIAL APPLICABILITY

The composition according to the present invention, viz.2,6-dimethyl-3,5-dimethoxycarbonyl-4-(5'-trimethylsilyl-2'-furyl)-1,4-dihydropyridinecan be useful in the pharmaceutical industry for the manufacture of amedicated preparation intended for the treatment of the hypertensivedisease.

We claim: 1.2,6-dimethyl-3,5-dimethoxycarbonyl-4-(5'-trimethylsilyl-2'-furyl)-1,4-dihydropyridineof the formula: ##STR3##